We have shown that endothelium dependent vascular relaxation is abnormal in hypertensive patients. To further investigate the role of this endothelial dysfunction in essential hypertension, we studied the forearm vasculature response to intra-arterial infusion of the endothelium-dependent vasodilator acetylcholine, and the direct smooth muscle dilator sodium nitroprusside in 15 patients (age 54+/-12 yrs). Patients were studied while normotensive (mean blood pressure 93/-+9 mmHg, half on treatment and half with drugs stopped 5 half lives before the study), and while hypertensive (mean blood pressure 118+/-7 mmHg, after withdrawal of medications for at least 2 weeks). The results were compared to a group of normal volunteers, matched for age and sex. The increase in blood flow and the decrease in vascular resistance with acetylcholine was significantly reduced in hypertensive patients while they were off medications compared to normal controls. However, no significant differences were found between the two groups in the vascular responses to sodium nitroprusside. Medical therapy effectively normalized the blood pressure in each hypertensive patient. No significant differences were observed with regard to increase in blood flow and decrease in vascular resistance with acetylcholine in hypertensive patients between the two studies. Similarly, the vascular response to sodium nitroprusside did not differ between the two studies. Thus, the abnormal endothelium-dependent vascular relaxation observed in patients with essential hypertension is not improved when blood pressure is normalized with treatment. This finding suggests that such endothelial dysfunction either plays a primary causal role in the hypertensive process or, if secondary, becomes irreversible once this process is established.